Glucocorticoid hormones regulate higher cognitive and emotional function in man. These hormones signal through adrenocorticosteroid receptor molecules that target DNA, acting as gene transcription factors. In brain, these factors modulate expression of genes involved in neuronal signaling and plasticity and are ultimately critical for functions such as stress integration and memory. These functions are controlled by the hippocampus, a brain region that serves as a prime target for circulating glucocorticoids. Given the potential for adrenocorticosteroid receptors to integrate hormonal signals with environmental cues, adequate maintenance of glucocorticoid responsiveness is vital for hippocampal function. Traditionally, the impact of glucocorticoids on hippocampal function was thought to be uniformly negative. However, recent data suggest that physiological levels of glucocorticoids are important for hippocampal signaling and information processing. Recent studies in our laboratory further indicate that the aged hippocampus is relatively insensitive to glucocorticoids in aging, and it is loss rather than gain of glucocorticoid action that fuels hippocampal dysfunction. This proposal therefore addresses the novel hypothesis that age-related hippocampal deficits are caused by a failure of the glucocorticoid receptor to signal in the cell nucleus, resulting in impaired DNA binding and reduced transcription of genes responsible for hippocampal signaling and synaptic plasticity. Specific Aim 1 will test the hypothesis that age-related memory impairment and stress dysregulation are fueled by reductions in nuclear GR signaling. Specific Aim 2 is designed to determine the mechanism of age-related glucocorticoid receptor translocation deficits, evaluating interaction between the glucocorticoid receptor and its nuclear chaperone complex; translocation of the receptor-chaperone complex to the nucleus; nuclear export of the glucocorticoid receptor; and nuclear degradation. Specific Aim 3 will test the hypothesis that aging decreases transcription of glucocorticoid-regulated genes in a manner predictive of reduced glucocorticoid responsiveness. Together, these studies should provide novel information [on] glucocorticoid signaling mechanisms in brain, and provide potential targets for therapies aimed at minimizing the impact of glucocorticoid-related cellular dysfunction in aging.